Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up

BACKGROUND: The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods. METHODS: The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years. RESULTS: In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients. CONCLUSIONS: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy.     

Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib

BACKGROUND: Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS: The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/day, plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS: A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS: The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.     

Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia

BACKGROUND: Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP). METHODS: Patients received decitabine 15 mg/m(2) intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing. RESULTS: Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% +/- 0.9% (mean +/- standard error of the mean) to 60.4% +/- 2.0% on Day 5, 60.5% +/- 1.8% on Day 12, and returned to 68.8% +/- 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12. CONCLUSIONS: Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.     

Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT).

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.     

A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase

Imatinib is the single most effective agent in chronic myelogenous leukemia (CML) in blast phase (BP), inducing hematologic responses in 30 - 50% of patients. However, only a few of these are complete (CHR) and durable. Imatinib is synergistic with idarubicin and cytarabine. We administered imatinib 600 mg/day, cytarabine 10 mg/day subcutaneous, and idarubicin 12 mg/m² intravenous every 14 days in 19 patients with CML in myeloid BP. Fourteen patients (74%) achieved a hematologic response: CHR in 9 (47%) (3 with complete and 1 with minor cytogenetic responses) and return to chronic phase (RTC) in 5 (26%). Median duration of response was 10 weeks (range, 2 - 89). Six patients received allogeneic stem cell transplantation: 4 CHR, 1 chronic phase and 1 BP. Median survival was 5 months (range, 2 - 20 months). This outpatient regimen is effective and well tolerated and perhaps superior to single-agent imatinib for patients in myeloid BP.     

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

PURPOSE: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. EXPERIMENTAL DESIGN: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. RESULTS: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.     

格列卫治疗20例慢性粒细胞白血病临床观察

目的：评价格列卫治疗慢性粒细胞白血病(CML)的效果和不良副作用。方法：CML慢性期(CP)患者口服格列卫400mg/d。CML加速期、急变期(BC)患者口服格列卫400mg-600mg/d。结果：11例CML-CP患者均取得血液学完全缓解(HCR)。9例CML-AP和CML-BC患者4例取得HCR(37％)。7例CML-CP患者在3个月～6个月内4例取得遗传学完全缓解(56％)。CML—CP患者Ⅲ级白细胞(WBC)减少1例,血小板(BPC)减少2例。CML-AP和CML-BC患者,4例发生Ⅲ级-Ⅳ级WBC减少和BPC减少。而非血液学不良副作用,无Ⅲ级或Ⅳ级以上的毒副作用。结论：格列卫治疗CML-CP具有较高的HCR和细胞遗传学反应,CML-BC患者亦可取得较好的血液学反应。格列卫不良副作用发生率低．尤其CML-CP患者为安全。而CML-AP和CML-BC患者治疗期间,需加强支持治疗。     

伊马替尼治疗慢性粒细胞白血病的远期疗效观察

目的探讨伊马替尼治疗慢性粒细胞白血病(CML)的长期疗效及影响CML患者生存的因素。方法对66例CML患者应用伊马替尼治疗,检测血常规、染色体核型、bcr/abl转录本表达及不良反应情况。结果中位随访39(6～84)个月。CML慢性期患者完全血液学缓解(CHR)率为95.8%,主要细胞遗传学缓解(MCyR)率为75.0%,完全细胞遗传学缓解(CCyR)率为68.8%,完全分子学缓解(CM0R)率为41.7%,均显著高于加速期及急变期(P<0.01)。慢性期患者3、5和7年总生存(OS)率分别为95.3%、90.3%和87.5%,疾病无进展生存(PFS)率分别为91.6%、84.5%和81.3%;加速期患者1、2和3年OS率分别为90.5%、37.6%和37.6%;1、2和3年的预期PFS率分别为37.2%、28.4%和17.6%;急变期患者6、12、18个月的预期OS率分别为83.6%、32.3%和32.3%。慢性期患者与加速期、急变期患者OS及PFS比较差异有统计学意义(P<0.01);多因素分析结果显示,应用伊马替尼治疗前接受过其他治疗是影响PFS的不利因素。结论伊马替尼对CML慢性期疗效显著优于加速期及急变期;慢性期患者达到CCyR甚至CM0R,是获得长期生存的关键。     

Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal

BACKGROUND: Several staging classification systems, all of which were designed in the preimatinib era, are used for chronic myeloid leukemia (CML). The World Health Organization (WHO) recently proposed a new classification system that has not been validated clinically. The authors investigated the significance of the WHO classification system and compared it with the classification systems used to date in imatinib trials ("standard definition") to determine its impact in establishing the outcome of patients after therapy with imatinib. METHODS: In total, 809 patients who received imatinib for CML were classified into chronic phase (CP), accelerated phase (AP), and blast phase (BP) based on standard definitions and then were reclassified according to the new WHO classification system. Their outcomes with imatinib therapy were compared, and the value of individual components of these classification systems was determined. RESULTS: With the WHO classification, 78 patients (10%) were reclassified: 45 patients (6%) were reclassified from CP to AP, 14 patients (2%) were reclassified from AP to CP, and 19 patients (2%) were reclassified from AP to BP. The rates of complete cytogenetic response for patients in CP, AP, and BP according to the standard definition were 72%, 45%, and 8%, respectively. After these patients were reclassified according to WHO criteria, the response rates were 77% (P = 0.07), 39% (P = 0.28), and 11% (P = 0.61), respectively. The 3-year survival rates were 91%, 65%, and 10%, respectively, according to the standard classification and 95% (P = 0.05), 63% (P = 0.76), and 16% (P = 0.18), respectively, according to the WHO classification. Patients who had a blast percentage of 20-29%, which is considered CML-BP according to the WHO classification, had a significantly better response rate (21% vs. 8%; P = 0.11) and 3-year survival rate (42% vs. 10%; P = 0.0001) compared with patients who had blasts > or = 30%. CONCLUSIONS: Different classification systems had an impact on the outcome of patients, and some prognostic features had different prognostic implications in the imatinib era. The authors believe that a new, uniform staging system for CML is warranted, and they propose such a system.     

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

BACKGROUND:

In patients with chronic‐phase chronic myeloid leukemia (CP‐CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325‐fold more potent inhibition than imatinib against unmutated Bcr‐Abl in vitro. Data with a minimum of 2 years of follow‐up were available for the current study of dasatinib and high‐dose imatinib in CP‐CML resistant to imatinib at daily doses from 400 mg to 600 mg.

METHODS:

A phase 2, open‐label study was initiated of 150 patients with imatinib‐resistant CP‐CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high‐dose imatinib 800 mg (400 mg twice daily; n = 49).

RESULTS:

At a minimum follow‐up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high‐dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high‐dose imatinib (29% vs 12%; P = .028). The estimated progression‐free survival also favored dasatinib (unstratified log‐rank test; P = .0012).

CONCLUSIONS:

After 2 years of follow‐up, dasatinib demonstrated durable responses and improved response and progression‐free survival rates relative to high‐dose imatinib. Cancer 2009. © 2009 American Cancer Society.     

U.S. Food and Drug Administration Approval Summary: Omacetaxine Mepesuccinate as Treatment for Chronic Myeloid Leukemia

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com ) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single‐arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit‐to‐risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.     

Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib

PURPOSE: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. EXPERIMENTAL DESIGN: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. RESULTS: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. CONCLUSIONS: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.     

Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia

BACKGROUND:

Although many patients with chronic myeloid leukemia (CML) respond well to imatinib therapy, a significant proportion loses their initial response. Loss of response on imatinib is often because of BCR‐ABL mutations. Dasatinib is a 325‐fold more potent inhibitor of Bcr‐Abl than imatinib and has been associated with high rates of durable responses in patients with CML in chronic phase (CP) after imatinib failure.

METHODS:

To determine the optimal time for initiating dasatinib after loss of response on imatinib, data from dasatinib trials in CML‐CP were analyzed. Patients were grouped according to whether they received early intervention with dasatinib (ie, after cytogenetic recurrence on imatinib), rather than after both cytogenetic and hematologic recurrence.

RESULTS:

Overall, 72% of patients who received dasatinib after loss of a major cytogenetic response (MCyR) on imatinib achieved a complete cytogenetic response (CCyR) compared with 42% of patients who were treated after loss of both MCyR and complete hematologic response (CHR). Event‐free survival (EFS) also was higher after earlier dasatinib treatment (24‐month EFS rates: 89% after loss of MCyR on imatinib vs 29% after loss of both MCyR and CHR). Among patients who were treated after loss of CHR on imatinib with no prior MCyR, 26% achieved a CCyR with dasatinib, and the 24‐month EFS rate was 64%. In all 3 groups, CCyR rates were similar in patients with or without pre‐existing BCR‐ABL mutations.

CONCLUSIONS:

The results of the current study suggested that optimal outcomes are achieved when dasatinib is administered early after imatinib resistance. Cancer 2009. © 2009 American Cancer Society.     

Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment

Thirty-five patients with Ph+ CML aged more than 60 years were treated with imatinib. Twenty-four patients (group A) were in late chronic phase (CP) and eleven patients (group B) were in accelerated/blastic phase (AP/BP). In group A, complete haematological response (CHR) was achieved by all patients; seventeen patients (70.8%) attained a complete cytogenetic response (CCR), one (4.1%) attained a partial CR, one (4.1%) a minor CR (Ph+ 70%) and five (21%) were resistant (Ph+ 100%), toxicity was mild: seven patients had a transient cytopenia, three a skin reaction, one a moderate oedema and one muscular pain. After a median follow-up of 15 months, 1 patient died in progression and 23 patients are alive (2 in BP and 21 in persisting response). In group B, one patient died after 3 months in aplastic phase from sepsis, three patients were resistant and seven patients (63.7%) achieved CHR; of these, four obtained CCR. After a median follow-up of 17 months, 4 patients have died from progressive disease, 6 are alive; 1 in AP and 5 in CHR (4 of them being in CCR). Present data indicate that imatinib is safe also in elderly with clinical results as good as in younger patients.     

甲磺酸伊马替尼治疗慢性粒细胞白血病的临床观察

目的:总结甲磺酸伊马替尼(IM)治疗Ph阳性慢性粒细胞白血病(CML)患者的临床观察体会。方法:收集110例Ph阳性CML慢性期(CP)患者、6例加速期(AP)患者和4例急变期(BC)患者分别口服IM 400、600或800 mg/d。通过血液学、细胞遗传学和分子遗传学指标来判断疗效。结果:CP患者完全血液学反应(CHR)率、主要细胞遗传学反应(MCyR)率和完全细胞遗传学反应(CCyR)率分别为98.2%、90.9%和80.9%;AP分别为66.7%、33.3%和16.7%,P值分别为0.002、0.000和0.000。其中CP患者中肝肾功能不全的患者需减少IM剂量。27例经干扰素治疗失败的CP患者IM治疗仍有效。第1年高随访(1次/月)CP患者CCyR达81.9%,非高随访则为63.6%,P=0.005 2。服药前肾功能不全和肝功能不全较脏器功能正常的CP患者服药6个月内发生3~4级血液学毒副反应概率增高,服药6个月后有所减少。结论:IM对CP患者包括干扰素治疗失败的有较高疗效,对AP和BC患者有一定近期疗效。肝肾功能不全的患者易出现血液学毒副反应,需要药物剂量调整。     

Expanding Nilotinib Access in Clinical Trials (ENACT): an open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase

BACKGROUND:

Nilotinib is a selective, potent BCR‐ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome‐positive chronic myeloid leukemia patients in chronic phase (CML‐CP) or accelerated phase who failed prior imatinib.

METHODS:

This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML‐CP (N = 1422).

RESULTS:

In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression‐free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re‐escalation, 87% successfully achieved re‐escalation to the full dose.

CONCLUSIONS:

This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society.     

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0-65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.     

Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose

Imatinib mesylate is the gold standard treatment of chronic myeloid leukaemia (CML) and 400 mg/day is considered the standard dose. Although it is generally well tolerated, some patients require temporary drug discontinuation and permanent dose reduction because of haematological or non‐haematological toxicities. Whether or not reduced doses are effective as the standard dose in inducing and/or maintaining complete cytogenetic and molecular response is not clear. We report the outcome of 45 CML patients in early (17) and late (28) chronic phase (CP) in whom, within a series of 250 patients treated with imatinib, reduced the dose of the drug after experiencing adverse events. Median time interval between the start of therapy and dose reduction was 58 days, whereas median administered dose was 300 mg/day. At 6 months from reduction, major cytogenetic responses (MCRs) were observed in 67% of patients, with 58% being complete cytogenetic remission (CCR), and complete molecular response (CMR) were obtained in 18% of patients. At 12 months, all patients who had obtained MCR reached CCR: this was significantly higher in low risk patients (87%) versus non‐low risk patients (66 and 46%), and in early phase (82%) versus late phase (53.5%). CMR and major molecular response (MMR) were detected in 20 and 22% of patients, respectively. Low dose imatinib appears effective in patients with intolerance to standard dose, even though long‐term effects remain to be established. Copyright © 2009 John Wiley & Sons, Ltd.     

甲磺酸马替尼治疗慢性髓细胞白血病急性髓性变的疗效

背景与目的:慢性髓细胞白血病急性髓性变后,治疗非常困难,预后极差。本文旨在探讨特异性BCR/ABL酪氨酸激酶抑制剂(甲磺酸马替尼,格列卫)治疗慢性髓细胞白血病急性髓性变的疗效。方法:甲磺酸马替尼治疗组19例与历史对照组22例均先用含阿糖胞苷的标准化疗方案诱导治疗2疗程后,治疗组用甲磺酸马替尼400mg/d继续巩固或诱导治疗,治疗4周如无效,则将剂量增加至600mg/d,继续治疗8周;如有效,则用该剂量继续维持,仍无效则停用。历史对照组则采用其他方案继续巩固或诱导治疗。结果:治疗组标准诱导治疗无效的16例患者用甲磺酸马替尼治疗,6例(38%)取得完全的血液学缓解,获大部分遗传学效应;2例(13%)获部分血液学缓解,1例(6%)回到慢性期,获小部分遗传学效应;总的血液学有效率为56%。存活1年者6例(38%)。对照组诱导治疗无效的18例患者采用其他方案诱导化疗,仅2例(11%)取得完全的血液学缓解;1例(6%)获部分血液学缓解,总有效率为17%;1年内存活者仅1例(6%)。两组比较,差异有显著性(P<0.05)。结论:甲磺酸马替尼治疗慢性髓细胞白血病急性髓性变疗效高、生存时间延长,且耐受性好。但仍存在复发和耐药问题。